Method for the preparation of citalopram

ABSTRACT

A method for the preparation of citalopram wherein the aldehyde of formula  
                 
 
     is converted to the corresponding 5-cyano compound of formula (I)  
                 
 
     which is alkylated to form citalopram, which is isolated in the form of the base or an acid addition salt thereof.

[0001] The present invention relates to a method for the preparation ofthe well-known antidepressant drug citalopram,1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran-carbonitrile.

BACKGROUND OF THE INVENTION

[0002] Citalopram is a well-known antidepressant drug that has now beenon the market for some years and has the following structure:

[0003] It is a selective, centrally acting serotonin(5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly havingantidepressant activities. The antidepressant activity of the compoundhas been reported in several publications, eg. J. Hyttel Prog.Neuro-Psychopharmacol. & Biol. Psychiat. 1982, 6, 277-295 and A. GravemActa Psychiatr. Scand. 1987, 75, 478-486. The compound has further beendisclosed to show effects in the treatment of dementia andcerebrovascular disorders, EP-A-474580.

[0004] Citalopram was first disclosed in DE 2,657,013, corresponding toU.S. Pat. No. 4,136,193. This patent publication describes thepreparation of citalopram by one method and outlines a further methodwhich may be used for preparing citalopram.

[0005] According to the process described, the corresponding1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile is reactedwith 3-(N,N-dimethylamino)propyl-chloride in the presence ofmethylsulfinylmethide as condensing agent. The starting material wasprepared from the corresponding 5-bromo derivative by reaction withcuprous cyanide.

[0006] International patent application No. WO 98/019511 discloses aprocess for the manufacture of citalopram wherein a (4-(cyano,alkyloxycarbonyl oralkylaminocarbonyl)-2-hydroxymethylphenyl-(4-fluorophenyl)methanolcompound is subjected to ring closure. The resulting 5-(alkyloxycarbonylor alkylaminocarbonyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran isconverted to the corresponding 5-cyano derivative and the 5-cyanoderivative is then alkylated with a (3-dimethylamino)propylhalogenide inorder to obtain citalopram.

[0007] It has now, surprisingly, been found that citalopram may bemanufactured by a novel favourable process via1-(4-fluorophenyl)-1,3-dihydroisobenzofurane-5-formaldehyde prepared byring closure of2,4-dihydroxymethyl-1-[1-(4-fluorophenyl)-1-hydroxy-1-methyl]benzene andoxidation of the resulting5-hydroxymethyl-1-(4-fluorophenyl)-1,3-duhydroisobenzofuran.

SUMMARY OF THE INVENTION

[0008] The present invention thus relates to a method for thepreparation of citalopram wherein the aldehyde of formula

[0009] is converted to the corresponding 5-cyano compound of formula (I)

[0010] followed by alkylation to form citalopram, which is isolated inthe form of the base or as a pharmaceutically acceptable acid additionsalt thereof.

[0011] In a particularly preferred embodiment of the invention, thecompound of formula (II) is prepared by reduction of a compound offormula

[0012] to form a compound of formula

[0013] followed by ring closure to form a compound having the formula

[0014] which, is then oxidised to form the compound of formula (II).

[0015] The invention also relates to the intermediate having the formula

[0016] or a salt thereof.

[0017] Finally, the invention relates to an antidepressantpharmaceutical composition comprising citalopram manufactured by aprocess of the invention.

[0018] According to a preferred embodiment of the invention, thealkylation is carried out by reaction of a compound of formula (1) witha 3-(dimethylamino)propylhalogenide as described in U.S. Pat. No.4,136,193.

DETAILED DESCRIPTION OF THE INVENTION

[0019] According to the present invention, the citalopram intermediateshaving the formulas (I) and (II) may be prepared by the processillustrated in the following reaction scheme:

[0020] The conversion of the compound of formula (III) to a compound offormula (V) may be carried out using conventional techniques. Thus, thereducing agent used for reduction of the compound of (III) may beLiAlH₄, NaAlH₂(OCH₂CH₂OMe)₂, NaBH₄/BF₃.Et₂O, NaBH₄/I₂ or any anothersuitable reducing agent, the ring closure of the compound of formula(IV) may be carried out by dehydration using mineral acids such asH₃PO₄, H₂SO₄, HCl or another suitable dehydrating agent or by ringclosure of the corresponding active ester in presence of a base asdescribed in EP 347 066. The oxidation of the compound of formula (V)may be carried out using MnO₂, NiO₂, (NH₄)₂Ce(NO₃)₆ or another suitableoxidixing agent.

[0021] Conversion of the formaldehyde group of the compound of formula(II) to a cyano group may be carried out by reaction with hydroxylaminefollowed by treatment with a dehydrating agent such as SOCl₂. Othermethods are described in WO 99/30548, see in particular page 6.

[0022] The compound of formula (III) may be prepared by oxidation of thecorresponding dimethyl compound as described in N. S. Dokunikhin, B. V.Salov, A. S. Glagoleva Zhurnal Obshchei Khimii 1964, 34, 995-998.

[0023] The alkylation of the compound of formula (I) to form citaloprammay be performed according to the process of U.S. Pat. No. 4,136,193 orWO 98/019611.

[0024] Alternatively, the alkylation may be carried our as described inco-pending DK application No PA 200000353.

[0025] According to this process, citalopram is prepared by alkylationof a compound of formula (I) with a compound having the formula

[0026] wherein R is halogen or —O—SO₂—X wherein X is alkyl, aryl,aralkyl or alkylaryl and R¹ is dimethylamino, —O—SO₂—X wherein X isalkyl, aryl, aralkyl or alkylaryl, or halogen; provided that R is nothalogen when R¹ is dimethylamino, followed by isolation of citalopramwhere R is dimethylamino, or followed by reaction of the resultingcompound of formula

[0027] wherein R² is halogen or a group of formula —O—SO₂—X wherein X isas defined above with dimethylamin or a metal salt thereof; andthereafter isolation of citalopram or a pharmaceutically acceptable acidaddition salt thereof.

[0028] The alkylation step where the compound of formula (I) is reactedwith a compound of formula (VI) is suitably carried out by treatment ofthe compound of formula (I) with a base such as for example LDA (lithiumdiisopropylamine), LiHMDS (lithium hexamethyldisilazane), NaH, NaHMDS(sodium hexamethyldisilazane), or NaOMe in an aprotic organic solventsuch as THF (tetrahydrofurane), DMF (dimethylformamide), NMP(N-methylpyrrolidon), ethers such as diethylether, or dioxalane,toluene, benzene, or alkanes and mixtures thereof. The anion formed isthen reacted with a compound of formula (VI) whereby a group of formula—CH₂—CH₂—CH₂—R² or a group of formula —CH₂—CH₂—CH₂—N(CH₃)₂ is introducedinto position 1 of the isobenzofuranyl ring system.

[0029] The compound of formula (VII) is then reacted with dimethylaminor a metal salt thereof, such as M⁺, ⁻N(CH₃)₂ wherein M⁺ is Li⁺ or Na⁺.The reaction is suitably carried out in an aprotic organic solvent suchas THF (tetrahydrofurane), DMF (dimethylformamide), NMP (N-methylpyrrolidon), ethers such as diethylether, or dioxalane, toluene,benzene, or alkanes and mixtures thereof.

[0030] The reaction conditions, solvents, etc. used for the reactionsdescribed above are conventional conditions for such reactions and mayeasily be determined by a person skilled in the art.

[0031] Other methods for the alkylation of a compound of formula (I) toform citalopram are described in co-pending DK application No 200000404.

[0032] According to the processes described herein, citalopram may beprepared by:

[0033] a) Reaction of a compound of formula (I) with a compound offormula HCO—(CH₂)₂—N(CH₃)₂ followed by dehydration to form a compound offormula (VIII)

[0034]  and reduction of the compound of formula (VIII) to formcitalopram;

[0035] b) Reaction of a compound of formula (I) with a compound offormula

[0036]  followed by dehydration to form a compound of formula (VIII) asabove and reduction to form citalopram; or

[0037] c) Reaction of a compound of formula (I) with a compound offormula Y—CH₂—CH═CH₂ wherein Y is a suitable leaving group to form acompound of formula

[0038] followed by peroxidation of the double bond and reaction withdimethyl amine to form a compound of formula (VIII) and reduction of thecompound of formula (VIII) to form citalopram.

[0039] The alkylation step where the compound of formula (I) with acompound of formula HCO—(CH₂)₂—N(CH₃)₂, Y—CH₂—CH═CH₂, or of formula (IX)is suitably carried out as described above for the reaction of acompound of formula (I) with a compound of formula (VI).

[0040] Other methods for alkylation of a compound of formula (I) to formcitalopram are described in co-pending DK applications Nos PA 200000401,PA 200000403, PA 200000404, PA 200000414 and PA 200000415.

[0041] Citalopram is on the market as an antidepressant drug in the formof the racemate. However, in the near future the active S-enantiomer ofcitalopram is also going to be introduced to the market.

[0042] S-citalopram may be prepared by separation of the opticallyactive isomers by chromatography.

[0043] Throughout the specification and claims, the term alkyl refers toa branched or unbranched alkyl group having from one to six carbon atomsinclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl,2-methyl-2-propyl, 2,2-dimethyl-1-ethyl and 2-methyl-1-propyl.

[0044] The term aryl refers to a mono- or bicyclic carbocyclic aromaticgroup, such as phenyl and naphthyl, in particular phenyl.

[0045] The term aralkyl refers to aryl-alkyl, wherein aryl and alkyl isas defined above.

[0046] Halogen means chloro, bromo or iodo.

[0047] Citalopram may be used as the free base or as a pharmaceuticallyacceptable acid addition salt thereof. As acid addition salts, suchsalts formed with organic or inorganic acids may be used. Exemplary ofsuch organic salts are those with maleic, fumaric, benzoic, ascorbic,succinic, oxalic, bismethylenesalicylic, methanesulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric,gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic,stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as the8-halotheophyllines, for example 8-bromotheophylline. Exemplary of suchinorganic salts are those with hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric and nitric acids.

[0048] The acid addition salts of the compounds may be prepared bymethods known in the art. The base is reacted with either the calculatedamount of acid in a water miscible solvent, such as acetone or ethanol,with subsequent isolation of the salt by concentration and cooling, orwith an excess of the acid in a water immiscible solvent, such asethylether, ethylacetate or dichloromethane, with the salt separatingspontaneously.

[0049] The pharmaceutical compositions of the invention may beadministered in any suitable way and in any suitable form, for exampleorally in the form of tablets, capsules, powders or syrups orparenterally in the form of usual sterile solutions for injection.

[0050] The pharmaceutical formulations of the invention may be preparedby conventional methods in the art. For example, tablets may be preparedby mixing the active ingredient with ordinary adjuvants and/or diluentsand subsequently compressing the mixture in a conventional tablettingmaschine. Examples of adjuvants or diluents comprise: Corn starch,potato starch, talcum, magnesium stearate, gelatine, lactose, gums, andthe like. Any other adjuvant or additive, colourings, aroma,preservatives etc. may be used provided that they are compatible withthe active ingredients.

[0051] Solutions for injections may be prepared by solving the activeingredient and possible additives in a part of the solvent forinjection, preferably sterile water, adjusting the solution to thedesired volume, sterilising the solution and filling it in suitableampoules or vials. Any suitable additive conventionally used in the artmay be added, such as tonicity agents, preservatives, antioxidants, etc.

[0052] The invention is further illustrated by the following examples.

EXAMPLE 1

[0053]1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile

[0054] Step 1:2,5-Dihydroxymethyl-1-[1-(4-fluoro-phenyl)-1-hydroxy-1-methyl]benzeneLiAlH₄ (15.2 g, 0.6 mole) is covered with toluene (800 mL). THF (400 mL)is added. 4-Fluorobenzophenone-2′, 4′-dicarboxylic acid¹) (58 g, 0.2mole) is added in portions of about 10 grams. The temperature is allowedto rise to 50° C. The mixture is heated at reflux temperature for 1½hour. After cooling to 10° C., water (100 mL) is added carefully. K₂CO₃(150 g) is added and the suspension is stirred for ½ hour. Afterfiltration the volatiles are evaporated off in vacuo. Yield (50 g, 95%).The title compound is obtained as an oil. ¹H NMR (DMSO-d₆, 500 MHz):4.28 (2H, s), 4.41 (2H, s), 5.75 (1H, s), 6.95-7.35 (7H).

[0055] Step 2: 5-Hydroxymethyl-1-(4-fluorophenyl)-I,3-dihydroisobenzofurane. H₃PO₄ (200 mL, 60%) is added to triol2,4-dihydroxymethyl-1-[1-(4-fluorophenyl)-1-hydroxy-1-methyl]-benzene(50 g) and the mixture is heated to 80° C. for 2 hours. On cooling, thetitle compound crystallises and is filtered off. Recrystallization fromEtOH/water ((1:3), 400 mL). Yield: 44 grams (90%, total for step 1 and2). Mp: 101-03 C. ¹H NMR (DMSO-d₆, 500 MHz): 4.51 (2H, s), 5.08 (1H, dJ=12.5 Hz), 5.26 (1H, d J=12.5 Hz), 6.14 (1H, s), 6.96-7.4 (7H).

[0056] Step 3:1-(4-Fluorophenyl)-1,3-dihydroisobenzofurane-5-formaldehyde.

[0057] The hydroxymethyl phthalan5-hydroxymethyl-1-(4-fluorophenyl)-1,3-dihydroisobenzofurane (24 grams,0.1 mole) is dissolved in DCM (500 mL). MnO₂ (52 grams) is added inthree portions. The mixture is stirred for 16 hours at room temperature.After filtration using a pad of filter help and silica the solvent isevaporated off in vacuo and the title compound is obtained as an oil.Yield: 24 g (100%). ¹H NMR (CDCl₃, 500 MHz): 5.22 (1H, d J=12.5 Hz),5.36 (1H, d J=12.5 Hz), 6.15 (1H, s), 7.0-7.73 (7H), 10.00 (1H,s).

[0058] Step 4:1-(4-Fluorophenyl)-1,3-dihydroisobenzofurane-5-carbonitrile.

[0059] To aldehyde1-(4-fluorophenyl)-1,3-dihydroisobenzofurane-5-formaldehyde (2.4 grams,0.01 mole) dissolved in EtOH (10 mL) is added NH₂OH,HCl (1 gram, 0.015mole) and NaOH (0.6 gram, 0.015 mole) dissolved in water (25 mL). Themixture is heated at reflux temperature for ½ hour. After cooling toroom temperature, the reaction mixture is left for 2 hour. The crystalsare filtered off and washed with cold water (2×10 mL) and dried. Theoxime is suspended in toluene (10 mL) and SOCl₂ (1.3 mL) is added. Themixture is heated to 80° C. for 1 hour. After cooling, the volatiles areevaporated off in vacuo and the title compound is crystallized fromheptane. Yield: 2.0 gram (84%) DSC (onset): 98 C.

[0060]¹⁾ N. S. Dokunikhin, B. V. Salov, A. S. Glagoleva Zhurnal ObshcheiKhimii 1964, 34, 995-998.

1. A method for the preparation of citalopram wherein the aldehyde offormula

is converted to the corresponding 5-cyano compound of formula (I)

which is alkylated to form citalopram, which is isolated in the form ofthe base or an acid addition salt thereof.
 2. The method according toclaim 1 wherein the compound of formula (II) is prepared by reduction ofa compound of formula

to form a compound of formula

followed by ring closure to form a compound having the formula

which is then oxidised to form the compound of formula (II)
 3. Themethod of claim 1 wherein the alkylation is made by reaction of thecompound of formula I with a 3-(dimethyl amino)propyl halogenide.
 4. Acompound having the formula

or an acid addition salt thereof.
 5. An antidepressant pharmaceuticalcomposition comprising citalopram manufactured by the process of any ofclaims 1 to 3.